BODIPY-Derived Photoremovable Protecting Groups Unmasked with Green Light

Article abstract of DOI:10.1021/jacs.5b01297

Photoremovable protecting groups derived from meso-substituted BODIPY dyes release acetic acid with green wavelengths >500 nm. Photorelease is demonstrated in cultured S2 cells. The photocaging structures were identified by our previously proposed strategy of computationally searching for carbocations with low-energy diradical states as a possible indicator of a nearby productive conical intersection. The superior optical properties of these photocages make them promising alternatives to the popular o-nitrobenzyl photocage systems.

Full text of DOI:10.1021/jacs.5b01297

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Communication
pubs.acs.org/JACS
BODIPY-Derived Photoremovable Protecting Groups Unmasked with
Green Light
Pratik P. Goswami, Aleem Syed, Christie L. Beck, Toshia R. Albright, Kaitlyn M. Mahoney, Ryan Unash,
Emily A. Smith,* and Arthur H. Winter*
Department of Chemistry, Iowa State University, 2101d Hach Hall, Ames, Iowa 50011, United States
*
S Supporting Information
development of new photocages that absorb visible light is the
lack of a structure−reactivity relationship for excited state
heterolysis. That is, it is difficult to predict a priori which
structures, when irradiated with light, will undergo an efficient
photoheterolysis reaction. Thus, attempts to prepare visible light
absorbing photocages have mostly bypassed this problem by
ABSTRACT: Photoremovable protecting groups derived
from meso-substituted BODIPY dyes release acetic acid
with green wavelengths >500 nm. Photorelease is
demonstrated in cultured S2 cells. The photocaging
structures were identified by our previously proposed
strategy of computationally searching for carbocations with
low-energy diradical states as a possible indicator of a
nearby productive conical intersection. The superior
optical properties of these photocages make them
promising alternatives to the popular o-nitrobenzyl
photocage systems.
42−44
using metal−ligand photoreleasing systems
or by using
creative indirect schemes. Examples of such creative schemes
include upconverting nanoparticles with surface-attached UV-
4
5−47
absorbing photocages,
uncaging processes,
using multiphoton absorption
or release mediated by photoinduced
4
8−50
5
1
electron transfer with a sacrificial electron donor.
However, visible light absorbing organic structures that offer
simple photorelease schemes and structures would potentially
make a more compelling case for widespread use in biologically
hotoremovable protecting groups, sometimes called
52
P
photocages or phototriggers, are popular light-sensitive
chemical moieties that mask substrates through covalent linkages
that render the substrates inert. Upon irradiation, the masked
substrates are released, restoring their reactivity or function.
While photocages have important applications in areas such as
oriented laboratories. A recent computational study performed
in our lab suggested the hypothesis that photoheterolysis
53
reactions may be under conical intersection control. That is,
photoheterolysis of C-LG (carbon-leaving group) bonds to
54
generate ion pairs may be favored if the ion pair has access to a
nearby productive conical intersection that provides an efficient
channel for the excited state of the photoprecursor to decay to
the ground-state ion pair. Because conical intersections are
challenging to compute, we further suggested using the vertical
energy gap of the carbocation to its first excited state as a simple
1
−3
4,5
organic synthesis,
organic materials,
photolithography, and light-responsive
6
−8
these structures are particularly prized for
their ability to trigger biological activity with high spatial and
9
−13
temporal resolution.
Examples of such chemical tools
14−16
17,18
19−23
include photocaged proteins,
nucleotides,
ions,
fluorescent
(e.g., caged ATP). These
2
4,25
26,27
neurotransmitters,
pharmaceuticals,
predictor of a nearby conical intersection (CI). A low S
energy gap of the cation would suggest the possibility of a nearby
CI between the S and S surfaces and the potential for a
0
−S
1
2
8−30
31,32
dyes,
and small molecules
biologically relevant caged molecules and ions can be released
from the caging structure within particular biological micro-
environments using pulses of focused light. The most popular
photocages used in biological studies are the o-nitrobenzyl
0
1
productive mechanistic channel for the photochemistry to
proceed from the excited state of the photocaged precursor to
the ion pair.
Thus, to find visible light absorbing photocages we searched
for potential photocaging structures that would generate
carbocations with low-lying diradical states. A time-dependent
density functional theory (TD-DFT) computational investiga-
tion of carbocations attached to the BODIPY scaffold at the meso-
position indicated that these ions have low-lying excited states.
3
1−33
systems
and their derivatives, but other photocages that see
34
35
significant use include those based on the phenacyl, acridinyl,
benzoinyl,
yl structures. Unfortunately, with few exceptions,
3
6,37
38
39
coumarinyl, xanthenyl, and o-hydroxynaphth-
4
0
41,42
a serious
limitation of the most popular photocages is that they absorb
light mostly in the ultraviolet where the limited penetration of
UV light into tissues largely restricts these studies to fixed cells
and thin tissue slices. Furthermore, prolonged exposure of cells
or tissues to UV light can lead to cellular damage or death.
Consequently, new photocaging structures that absorb visible
light are urgently needed. Advantages of visible light irradiation
include diminished phototoxicity compared to UV light and
deeper optical penetration into tissue. Additionally, visible light
photolysis can be performed with cheap lamps and Pyrex
glassware, while UV photolysis requires expensive UV sources.
Unfortunately, the major problem that has hindered the
For example, the TD-DFT computed S −S vertical energy gap
0
1
of the carbocation derived from C−O scission of 2 is 8 kcal/mol
TD-B3LYP/6-311+G (2d,p), suggesting a near-degenerate
(
diradical configuration. Indeed, all of the cations derived from
C−O scission of 1−6 have vertical gaps <13 kcal/mol (see SI for
computational details) and have singlet states with considerable
diradical character. Large singlet stabilizations upon switching
Received: February 5, 2015
Published: March 9, 2015
©
2015 American Chemical Society
3783
DOI: 10.1021/jacs.5b01297
J. Am. Chem. Soc. 2015, 137, 3783−3786

Journal of the American Chemical Society
Communication
from restricted → spin-purified unrestricted singlet computa-
tions indicate that the singlet states can be described as diradicals
or possessing considerable diradical character (see SI for details).
Thus, the exact vertical energies from the TD-DFT computa-
tions are to be viewed with suspicion, but it is clear that there are
low-energy diradical forms for these ions, suggesting a nearby CI
between the closed-shell singlet and singlet diradical forms of the
carbocations in the vicinity of the ion pair geometry. Further, the
singlet−triplet gaps of all the carbocations derived from 1−6 are
compute the quantum yields of photorelease (Φ), the flux of a
532 nm laser excitation beam (ND:YAG) was determined using
potassium ferrioxalate actinometry. Release of acetic acid as a
function of laser irradiation time in MeOH was followed by
quantitative LC/UV (see SI for details). Each quantum yield
reported is the average of three separate runs. Essentially
identical actinometry measurements performed after photolysis
demonstrated high flux stability of the laser. Additionally,
repeating the quantum yield measurement for 2 on a different
day with a different laser power setting (in triplicate) gave
essentially the same value for the quantum yield, indicating
reproducibility. A preparative photolysis of 2 in MeOH gave a
meso-substitued methyl ether adduct as a stable photoproduct of
the photocaging moiety, suggestive of solvent trapping of an
intermediate carbocation. Mass spec studies of the photo-
products also indicate trace amounts of a deborylated BODIPY
photoproduct as well as BODIPY dimers, possibly arising from
the diradical nature of the “carbocations” formed from
heterolysis leading to coupling processes. Additionally, lamp
photolysis of 2 showed no major difference in release of acetic
acid under argon or air atmosphere. Curiously, unlike 1−4 and 6,
the brominated compound 5 was found to be unstable. It
decomposes after 1 day stored on the shelf in the dark, and
photolysis of freshly prepared and purified 5 led to secondary
products in addition to acetic acid release, and photolysis was
accompanied by rapid solution bleaching. Consequently, we
were not confident in our quantum yield measurements for 5 and
excluded it from Table 1. Probably, 5 also has access to
alternative photochemical pathways (e.g., C−Br homolysis) and
thermal degradation channels similar to benzyl-based photoc-
∼
5 kcal/mol in favor of the triplet state, suggesting that the
carbocations” produced by heterolysis of 1−6 may in fact be
better described as ion diradicals in their thermodynamic ground
“
55
state than by traditional closed-shell carbocation structures.
Encouraged by these computational studies, we synthesized
structures 1−6 as photocages for acetic acid (Figure 1).
6
0
ages, which include bromine. In contrast, photocaged
compounds 1−4 and 6 are thermally stable in the dark. Boiling
these compounds in MeOH for 1 h in a foil-wrapped vessel led to
Figure 1. (a) Possible pathway for the photolysis of photocaged acetic
acid; (b) substrates described in this study.
1
no change in the H NMR spectrum (see SI for spectra).
In general, the quantum efficiencies for 1−4 and 6 are lower or
Advantages of the BODIPY scaffold include simple syntheses,
comparable with the popular caged o-nitrobenzyl or coumarinyl
56
9
a compact structure, known biological compatibility and high
systems. Quantum yields for 1−4 are lower than those for
57
extinction coefficients in the visible. Other recent studies have
typical o-nitrobenzyl photocaged structures or coumarinyl
systems, but this lower quantum yield is partially compensated
by the higher extinction coefficients of the BODIPY
chromophores compared to the o-nitrobenzyl chromophore,
leading to practically useful quantum efficiencies. The iodinated
derivative 6 has the largest quantum efficiency, comparable to
that of some caged o-nitrobenzyl systems, but with a λmax at ∼550
nm rather than in the UV (the parent o-nitrobenzyl system has a
5
8
shown BODIPYs can be used as laser dyes and have
59
photochemical heterolysis reactivity at boron. Photorelease
studies, described below, indicate that these structures release
carboxylic acids upon photolysis with wavelengths >500 nm.
Photorelease studies and quantum efficiencies. The observed
substrate release rate as a function of photolysis time is quantified
by the quantum efficiency parameter (εΦ), which is the product
of the extinction coefficient at the irradiation wavelength (ε) and
the quantum yield of release (Φ). Extinction coefficients for 1−6
were determined by UV−vis spectroscopy (see Table 1). To
λmax of ∼280 nm while a popular dimethoxy analogue has a λ
max
of ∼350 nm), although still much lower than the best known
photocaging systems. A plausible explanation for the higher
quantum yield of 6 is that the iodine atoms promote intersystem
crossing (ISC) to a triplet state, which are usually longer lived
than singlet excited states, giving more time for release. For
example, the phenacyl photocage derivatives described by Givens
a
Table 1. Optical Properties and Quantum Efficiencies of 1−6
4
λmax
λem
(nm)
ε (×10
εΦ
−
1
cm−1)
Φ (×10−4
)
(M−1 cm−1)
(
nm)
M
34
undergo photorelease in the triplet state. The plausibility of a
rapid ISC event is supported by the very weak fluorescence of
solutions of 5 and 6, compared to solutions of 1−4.
1
2
3
4
5
6
519
515
544
544
545
553
527
526
560
570
575
576
5.7
6.4
9.9
9.5
4.0
37
70
59
19
7.1
6.2
4.8
Optical properties of 1−6. The UV−vis spectra and
fluorescence spectra of 1−6 are shown in Figure 2. These
structures absorb between 515 and 553 nm (and emit between
4.9
23.8
117
5
20 and 580 nm), typical of simple BODIPY dyes, and feature
−1
−1
a
large extinction coefficients (∼50 000−70 000 M cm at λmax
Quantum yields of acetic acid release (Φ) determined by ferrioxalate
in MeOH).
actinometry in MeOH with a 532 nm ND:YAG laser source and
release followed using quantitative LC-UV (Φ values are the average of
Cell studies. To test the viability and usefulness of the
BODIPY derived photocages in biological systems, compound 7
3
runs).
3
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DOI: 10.1021/jacs.5b01297
J. Am. Chem. Soc. 2015, 137, 3783−3786

Journal of the American Chemical Society
Communication
Figure 2. Normalized absorbance and fluorescence spectra of 1−6.
6
1
was synthesized. 2,4-Dinitrobenzoic acid is a known
fluorescence quencher for BODIPY dyes. This quencher was
coupled with our BODIPY moiety using a standard DCC/
DMAP ester coupling reaction. We anticipated that 7 would be
weakly fluorescent, but upon photorelease of the quencher the
fluorescence would increase. Indeed, when 7 was irradiated with
a mercury lamp (excitation = 500 nm, see SI) in a cuvette and its
fluorescence was plotted over time (Figure 3N), there was a
growth in fluorescence attributed to release of the quencher.
Figure 3. Fluorescence images of S2 cells with no BODIPY compound
(A−D), cells incubated with compound 2 (E−H), and cells incubated
with compound 7 (I−L) as a function of irradiation time (top). Scale bar
is 20 μm (shown in panel A) and is the same for all the images. Images
were adjusted to same contrast in each row. Average of at least 32 cells
fluorescence intensity profile versus irradiation time using 100% lamp
power for excitation in cells (M). Increase in free BODIPY fluorescence
signal over time with quencher release from compound 7 in BES buffer
(N). Plot insert (N) depicts the difference in growth of fluorescence vs
time for compound 7 with (i) and without (ii) light irradiation in a
cuvette.
1
Photorelease of the quencher was confirmed by H NMR
photolysis studies. As a control, similar steady state fluorescence
measurements were performed over time for compound 7 in the
dark without light exposure, leading to essentially no change in
fluorescence.
Compound 2 and 7 were then incubated with Drosophila S2
cells and monitored using fluorescence microscopy (Figure 3A−
L). The Drosophilia S2 cells loaded with 2 and 7 were irradiated
continuously with 500 nm light. Fluorescence images were
collected every 36 ms for a total of 10.8 s. The fluorescence
intensity for compound 7 inside cell as shown in Figure 3I−L
increases rapidly. This increase in fluorescence can be attributed
to the release of the quencher. The same fluorescence study with
being easy to synthesize, utilizing a biocompatible chromophore,
and having superior optical properties to the most popular
photocages in current use. More generally, our strategy of
identifying new photocages by searching for carbocations with
low-energy diradical states seems to be a promising one.
BODIPY derivatives that release functional groups other than
carboxylic acids and that have red-shifted absorptions into the
biological window (∼600−1000 nm) are currently under
investigation.
2
as a control in Figure 3E−H shows no such increase in
fluorescence. For 2, the leaving group is acetate, which is not a
quencher. Thus, little change in the fluorescence would be
anticipated upon photorelease of acetic acid from this moiety.
The background decay in fluorescence for both 2 and 7 can be
attributed to photobleaching under the intense focused light.
Parts A−D of Figure 3 show that there is a minimal change in
fluorescence of cells when they are irradiated without being
loaded with compound 2 or 7. Figure 3M shows the fluorescence
intensity change over time for cells incubated with compound 2
and 7, and the control experiments without any compound.
Cytotoxicity of compounds were measured with trypan blue
exclusion assay. All values are normalized with the control cells
that were not incubated with any compound. At a compound
concentration of 25 μM, 97% for compound 2 and 92% for
compound 7 remained viable after 1 h.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Synthetic procedures and compound characterization data,
quantum efficiency determination details, laser photolysis data,
computational data, and cellular fluorescence movies. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Conclusion. BODIPY-derived photocages unmask carboxylic
acids with green light excitation >500 nm, and photocleavage can
be carried out in living cells. These photocages are promising
alternatives for the popular o-nitrobenzyl photocaging systems,
■
Corresponding Authors
*winter@iastate.edu
*esmith1@iastate.edu
3
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Journal of the American Chemical Society
Communication
Notes
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(
1
(
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̌
(39) Sebej, P.; Wintner, J.; Mu
̈
ller, P.; Slanina, T.; Al Anshori, J.;
, P.; Wirz, J. J. Org. Chem. 2013, 78, 1833.
A.H.W. thanks the Petroleum Research Fund and the Cottrell
Scholar Award from the Research Corporation for Scientific
Advancement for financial support. We are grateful to the lab of
Mark E. Thompson for providing us with an initial sample of 2
for preliminary testing. The fluorescence microscopy cellular
studies (EAS) were supported by National Science Foundation
grant CHE-1412084.
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